SIKE is an IKKε/TBK1-associated suppressor of TLR3-and virus-triggered IRF-3 activation pathways
SIKE is an IKKε/TBK1-associated suppressor of TLR3-and virus-triggered IRF-3 activation pathways
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DOI：
10.1038/sj.emboj.7600863
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发表时间：
2005-12-07
期刊：
影响因子：
11.4
通讯作者：
Shu, HB
中科院分区：
文献类型：
--
作者：
Huang, J;Liu, T;Shu, HB
病毒感染或TLR3参与导致转录因子IRF-3和NF-kappa B的激活，它们协同诱导I型IFN基因的转录。IKK epsilon和TBK1是两个IKK相关的激酶，在病毒和tlr3触发的IRF-3激活中起关键作用。我们发现了一种名为SIKE （IKK epsilon抑制因子）的蛋白质，它与IKK epsilon和TBK1相互作用。SIKE在生理状态下与TBK1相关，在病毒感染或TLR3刺激时与TBK1分离。SIKE的过表达破坏了IKK epsilon或TBK1与TRIF、RIG-I和IRF-3（病毒和tlr3触发的IRF-3激活途径中的成分）的相互作用，但没有破坏TRIF与TRAF6和RIP （tlr3触发的NF-kappa B激活途径中的成分）的相互作用。一致地，SIKE的过表达抑制病毒和tlr3触发的干扰素刺激反应元件（ISRE），但不抑制NF-kappa B的激活。SIKE增强病毒和tlr3的敲低触发ISRE，但不激活NF-kappa B。此外，SIKE的过表达抑制了IKK epsilon-和tbk1介导的抗病毒反应。这些发现表明SIKE是IKK epsilon和TBK1的生理抑制因子，并在病毒和tlr3触发的IRF-3通路中发挥抑制作用，而不是NF-kappa B激活途径。
Viral infection or TLR3 engagement causes activation of the transcription factors IRF-3 and NF-kappa B, which collaborate to induce transcription of type I IFN genes. IKK epsilon and TBK1 are two IKK-related kinases critically involved in virus- and TLR3-triggered activation of IRF-3. We identified a protein termed SIKE (for Suppressor of IKK epsilon) that interacts with IKK epsilon and TBK1. SIKE is associated with TBK1 under physiological condition and dissociated from TBK1 upon viral infection or TLR3 stimulation. Overexpression of SIKE disrupted the interactions of IKK epsilon or TBK1 with TRIF, RIG-I and IRF-3, components in virus- and TLR3-triggered IRF-3 activation pathways, but did not disrupt the interactions of TRIF with TRAF6 and RIP, components in TLR3-triggered NF-kappa B activation pathway. Consistently, overexpression of SIKE inhibited virus- and TLR3-triggered interferon-stimulated response elements (ISRE) but not NF-kappa B activation. Knockdown of SIKE potentiated virus- and TLR3-triggered ISRE but not NF-kappa B activation. Moreover, overexpression of SIKE inhibited IKK epsilon- and TBK1-mediated antiviral response. These findings suggest that SIKE is a physiological suppressor of IKK epsilon and TBK1 and plays an inhibitory role in virus- and TLR3-triggered IRF-3 but not NF-kappa B activation pathways.